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    Clinical Trial Results:
    A Randomized, Double Blind Comparison of the Effects of Atomoxetine versus Placebo on Neuropsychological Outcomes across the Day in Children with Attention-Deficit/Hyperactivity Disorder (ADHD) by Use of a Computer Based Continuous Performance Test (cb CPT).

    Summary
    EudraCT number
    		 2006-001470-25
    Trial protocol
    		 DE  
    Global end of trial date
    26 May 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Nov 2020
    First version publication date
    15 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    11148
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00546910
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon Fri 9 AM 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,
    Scientific contact
    Available Mon Fri 9 AM 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 May 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 May 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a two-arm, parallel, randomized, double-blind, placebo-controlled Phase 4 multicenter trial to compare the whole day efficacy of atomoxetine versus placebo in children aged 6 through 12 years with Attention-Deficit/Hyperactivity Disorder (ADHD) treated in an inpatient, day-patient and outpatient setting in Germany. Core symptoms will be measured during once or bi-weekly visits, three times per visit-day, by a computer based Continuous Performance Test. Following an initial 3-28-day screening and washout phase, patients will be assigned to double-blind treatment with atomoxetine or placebo. In the verum arm, a one-week atomoxetine treatment period with the 0.5 mg/kg per day lead-in dose will be succeeded by a 7 week period at the target dose of 1.2 mg/kg per day.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 125
    Worldwide total number of subjects
    125
    EEA total number of subjects
    125
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    117
    Adolescents (12-17 years)
    8
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 NA

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Atomoxetine
    Arm description
    		 0.5 milligram per kilogram (mg/kg) per day lead-in dose for 1 week followed by 7 weeks at 1.2 mg/kg per day dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atomoxetine
    Investigational medicinal product code
    LY139603
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 milligram per kilogram (mg/kg) per day lead-in dose for 1 week followed by 7 weeks at 1.2 mg/kg per day dose.

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to 1 week lead-in and 7 week standard target dose of atomoxetine.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to 1 week lead-in and 7 week standard target dose of atomoxetine.

    Number of subjects in period 1
    		Atomoxetine Placebo
    Started
    63
    62
    Completed
    54
    51
    Not completed
    9
    11
         Consent withdrawn by subject
    2
    -
         Physician decision
    -
    1
         Adverse event, non-fatal
    2
    3
         Lack of efficacy
    5
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atomoxetine
    Reporting group description
    		 0.5 milligram per kilogram (mg/kg) per day lead-in dose for 1 week followed by 7 weeks at 1.2 mg/kg per day dose.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to 1 week lead-in and 7 week standard target dose of atomoxetine.

    Reporting group values
    		 Atomoxetine Placebo Total
    Number of subjects
    		 63 62 125
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.1 ( 1.93 ) 8.9 ( 1.64 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 12 28
        Male
    		 47 50 97
    Race/Ethnicity
    Units: Subjects
        Caucasian
    		 62 62 124
        African
    		 1 0 1
    Diagnosis
    Breakdown of Attention Deficit/Hyperactivity Disorder (ADHD) diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).
    Units: Subjects
        ADHD-Combined Type
    		 40 48 88
        ADHD-Predominantly Inattentive Type
    		 17 11 28
        ADHD- Predominantly Hyperactive-Impulsive
    		 6 3 9
    Number of Participants with Family History of ADHD
    Number of participants with at least one biological relative (mother, father, sibling [brother, sister] or grandparent) with ADHD.
    Units: Subjects
        At least one known relative with ADHD
    		 36 35 71
        None or missing
    		 27 27 54
    Number of Participants with Prior Therapy For Attention-Deficit/Hyperactive Disorder (ADHD)
    Summarizes number of participants who received previous medication and non-medication attention-deficit/hyperactive disorder (ADHD) therapy.
    Units: Subjects
        Previous treatment for ADHD
    		 26 27 53
        None or missing
    		 37 35 72
    Number of Participants with Psychiatric Comorbidities
    Summarizes the psychologic comorbidities of participants. Because some participants may have one or more comorbidities while others may not, the breakdown of psychiatric comorbidities by treatment group does not equal the overall baseline number of participants in each treatment group.
    Units: Subjects
        At least one psychiatric comorbidity
    		 25 25 50
        None or missing
    		 38 37 75
    Summary Of Participants' Living Arrangements
    Summarizes the participants' living arrangements according to where they live most of the time.
    Units: Subjects
        Nuclear Family (Biological Mother and Father)
    		 38 36 74
        Single Mother
    		 15 17 32
        Step Parent (One Biologic and one step parent)
    		 10 9 19
    Region of Enrollment
    Units: Subjects
        Germany
    		 63 62 125
    ADHD Rating Scale-IV Parent Version: Investigator Administered & Scored, Total Score
    ADHD Rating Scale-IV Parent Version: Investigator Administered & Scored (ADHD-RS-IV-PV:IR) measures the 18 symptoms contained in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of Attention-Deficit/Hyperactivity Disorder. Individual item scores range from 0 (none/never or rarely) to 3 (severe/very often). Total scores range from 0 to 54.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 37.30 ( 10.62 ) 36.68 ( 12.53 ) -
    Clinical Global Impressions - Severity Of Attention Deficit Hyperactive Disorder Score
    Clinical Global Impressions- Severity Of Attention Deficit Hyperactive Disorder (CGI-S-ADHD) measures severity of the patient's overall severity of ADHD symptoms (1=normal, not at all ill; 7=among the most extremely ill patients).
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 5.11 ( 1.02 ) 5.05 ( 1.11 ) -
    Time Since Initial Diagnosis Of ADHD
    Units: Years
        arithmetic mean (standard deviation)
    		 1.8 ( 2.23 ) 1.6 ( 1.89 ) -
    Time Since Onset Of ADHD Symptoms
    Units: Years
        arithmetic mean (standard deviation)
    		 4.9 ( 2.12 ) 5.2 ( 1.95 ) -
    Weekly Rating Of Evening & Morning Behavior-Revised-Investigator Rated (Total)
    Weekly Rating Of Evening & Morning Behavior-Revised-Investigator Rated (WREMB-R-Inv) measures the level of difficulty of 11 common morning or evening behaviors (e.g. getting out of bed, doing homework, sitting through dinner). Possible scores for each item range from 0 (no difficulty) to 3 (a lot of difficulty) with a Total score (maximum score=33), Morning subscore (maximum score=9), Evening subscore (maximum score=24), and Item 11 score which pertains to degree of difficulty falling asleep (maximum score=3).
    Units: Units on a scale
        arithmetic mean (standard deviation)
    		 21.70 ( 7.64 ) 21.58 ( 7.91 ) -

    End points

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    End points reporting groups
    Reporting group title
    Atomoxetine
    Reporting group description
    		 0.5 milligram per kilogram (mg/kg) per day lead-in dose for 1 week followed by 7 weeks at 1.2 mg/kg per day dose.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to 1 week lead-in and 7 week standard target dose of atomoxetine.

    Primary: Change From Baseline Computer-based Continuous Performance Test (cb- CPT; Qbtech AB, Sweden), Variable: Hyperactivity (Includes Time Active [TA], Distance [DIS], Area [AR], Microevents [ME], Motion Simplicity [MS]) Q-scores At Week 8

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    End point title
    		 Change From Baseline Computer-based Continuous Performance Test (cb- CPT; Qbtech AB, Sweden), Variable: Hyperactivity (Includes Time Active [TA], Distance [DIS], Area [AR], Microevents [ME], Motion Simplicity [MS]) Q-scores At Week 8
    End point description
    Infra-red camera tracks movement of head reflector on patient performing computer test. Hyperactivity test variables: TA=percent time patient moved>1 centimeter (cm)/second; DIS=path of movement (m); AR=total area (cm2) of movements; ME=number of position changes>1 mm; MS=degree (percent) of directional changes. Results are converted to Q-scores (age and sex-adjusted normalized scores with a mean=0 and standard deviation (SD)=1 in general population, expressing the probability determined by the Gamma function in terms of SD of Gaussian density). Higher scores reflect more severe symptoms. Analysis population description (APD): Full analysis population (N=125) including all randomized participants taking at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline, 8 weeks (W8)
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    63
    62
    Units: Q-scores
    arithmetic mean (standard deviation)
        Baseline: TA-Morning
    0.62 ( 1.27 )
    0.84 ( 0.84 )
        Baseline: TA- Noon
    0.65 ( 1.13 )
    0.76 ( 0.79 )
        Baseline: TA- Evening
    0.66 ( 1.26 )
    0.85 ( 0.83 )
        W8 Change: TA- Morning
    -0.32 ( 1.00 )
    0.06 ( 0.84 )
        W8 Change: TA- Noon
    -0.60 ( 1.13 )
    0.15 ( 0.74 )
        W8 Change: TA- Evening
    -0.55 ( 1.08 )
    0.03 ( 0.76 )
        Baseline: DIS- Morning
    1.41 ( 1.69 )
    1.62 ( 1.68 )
        Baseline: DIS- Noon
    1.55 ( 1.86 )
    1.62 ( 1.74 )
        Baseline: DIS- Evening
    1.47 ( 1.86 )
    1.75 ( 1.73 )
        W8 Change: DIS- Morning
    -0.51 ( 1.80 )
    0.38 ( 1.75 )
        W8 Change: DIS- Noon
    -1.06 ( 1.94 )
    0.49 ( 1.52 )
        W8 Change: DIS- Evening
    -0.87 ( 1.71 )
    0.07 ( 1.54 )
        Baseline: AR- Morning
    1.14 ( 1.65 )
    1.40 ( 1.56 )
        Baseline: AR- Noon
    1.25 ( 1.66 )
    1.45 ( 1.59 )
        Baseline: AR- Evening
    1.19 ( 1.81 )
    1.58 ( 1.67 )
        W8 Change: AR- Morning
    -0.38 ( 1.58 )
    0.39 ( 1.60 )
        W8 Change: AR- Noon
    -0.87 ( 1.70 )
    0.40 ( 1.18 )
        W8 Change: AR- Evening
    -0.71 ( 1.53 )
    -0.00 ( 1.45 )
        Baseline: ME- Morning
    0.97 ( 1.32 )
    1.15 ( 1.11 )
        Baseline: ME- Noon
    0.98 ( 1.29 )
    1.09 ( 1.19 )
        Baseline: ME- Evening
    0.94 ( 1.45 )
    1.18 ( 1.18 )
        W8 Change: ME- Morning
    -0.47 ( 1.42 )
    0.20 ( 1.19 )
        W8 Change: ME- Noon
    -0.82 ( 1.48 )
    0.28 ( 1.01 )
        W8 Change: ME- Evening
    -0.72 ( 1.41 )
    0.06 ( 1.06 )
        Baseline: MS- Morning
    0.21 ( 1.08 )
    0.38 ( 1.01 )
        Baseline: MS- Noon
    0.25 ( 1.12 )
    0.32 ( 0.95 )
        Baseline: MS- Evening
    0.22 ( 1.21 )
    0.35 ( 1.05 )
        W8 Change: MS- Morning
    -0.22 ( 1.29 )
    -0.04 ( 1.07 )
        W8 Change: MS- Noon
    -0.39 ( 1.37 )
    -0.12 ( 0.94 )
        W8 Change: MS- Evening
    -0.38 ( 1.31 )
    -0.19 ( 1.09 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.87
    Notes
    [1] - Superiority or Other (legacy)
    [2] - P-value is for Time Active overall for morning, noon and evening. Primary tests were performed hierarchically to adjust for multiplicity. Time Active was tested at rank 8. Positive values for the mean difference are in favor of the atomoxetine arm.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.57
    Notes
    [3] - Superiority or legacy
    [4] - P-value is for Distance overall for morning, noon and evening. Primary tests were performed hierarchically to adjust for multiplicity. Distance was tested at rank 5. Positive values for the mean difference are in favor of the atomoxetine arm.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.001 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.35
    Notes
    [5] - Superiority or legacy
    [6] - P-value is for Area overall for morning, noon and evening. Primary tests were performed hierarchically to adjust for multiplicity. Area was tested at rank 6. Positive values for the mean difference are in favor of the atomoxetine arm.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 < 0.001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.22
    Notes
    [7] - Superiority or legacy
    [8] - P-value is for Microevents overall for morning, noon and evening. Primary tests were performed hierarchically to adjust for multiplicity. Microevents was tested at rank 3. Positive values for the mean difference are in favor of the atomoxetine arm.
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.001 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 0.58
    Notes
    [9] - Superiority or legacy
    [10] - P-value is for Motion Simplicity overall for morning, noon and evening. Primary tests were performed hierarchically to adjust for multiplicity.Motion Simplicity was tested at rank 9. +ve values for the mean difference are in favor of the atomoxetine

    Primary: Change From Baseline cb CPT Variable: Inattention (Includes Reaction Time Variation[RTV], Omission Error [OR], Mean Reaction Time [mRT], Normalized Variation Of Reaction Time [nVRT]) Q-scores At Week 8

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    End point title
    		 Change From Baseline cb CPT Variable: Inattention (Includes Reaction Time Variation[RTV], Omission Error [OR], Mean Reaction Time [mRT], Normalized Variation Of Reaction Time [nVRT]) Q-scores At Week 8
    End point description
    Computer test. Patient is to press button if target appears, but not at non-target. Inattention test variables: mRT=average time (ms) from target presentation to response; RTV=standard deviation of mRT; nVRT=RTV expressed in terms of RT (variation as a percent of mean value); OE= percent of omitted targets. Results are converted to Q-scores (age and sex-adjusted normalized scores with a mean=0 and SD=1 in the general population, expressing the probability determined by the Gamma function in terms of SD of Gaussian density). Higher scores reflect more severe symptoms. APD: Full analysis population (N=125) including all randomized participants taking at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline, 8 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    63
    62
    Units: Q-scores
    arithmetic mean (standard deviation)
        Baseline: RTV-Morning
    2.93 ( 2.41 )
    2.49 ( 1.62 )
        Baseline: RTV-Noon
    2.95 ( 2.11 )
    2.48 ( 1.92 )
        Baseline: RTV-Evening
    2.63 ( 2.49 )
    2.19 ( 2.00 )
        W8: RTV-Morning
    -0.89 ( 2.29 )
    -0.09 ( 1.78 )
        W8: RTV-Noon
    -1.07 ( 1.92 )
    0.00 ( 1.70 )
        W8: RTV-Evening
    -0.90 ( 1.98 )
    -0.00 ( 1.88 )
        Baseline: OR- Morning
    1.12 ( 1.24 )
    1.13 ( 1.19 )
        Baseline: OR- Noon
    1.31 ( 1.32 )
    1.30 ( 1.32 )
        Baseline: OR- Evening
    1.22 ( 1.43 )
    1.28 ( 1.34 )
        W8: OR- Morning
    0.01 ( 1.83 )
    0.54 ( 1.14 )
        W8: OR- Noon
    0.03 ( 1.45 )
    0.53 ( 1.17 )
        W8: OR- Evening
    -0.04 ( 1.50 )
    0.52 ( 1.20 )
        Baseline: mRT- Morning
    2.42 ( 2.03 )
    1.92 ( 1.53 )
        Baseline: mRT- Noon
    2.40 ( 1.78 )
    2.02 ( 1.49 )
        Baseline: mRT- Evening
    2.23 ( 1.77 )
    1.86 ( 1.49 )
        W8: mRT- Morning
    -0.18 ( 1.84 )
    0.35 ( 1.28 )
        W8: mRT- Noon
    -0.35 ( 1.53 )
    0.12 ( 1.42 )
        W8: mRT- Evening
    -0.13 ( 1.40 )
    0.48 ( 1.37 )
        Baseline: nVRT-Morning
    1.00 ( 1.60 )
    0.93 ( 1.28 )
        Baseline: nVRT-Noon
    1.06 ( 1.48 )
    0.82 ( 1.26 )
        Baseline: nVRT-Evening
    0.92 ( 1.81 )
    0.68 ( 1.31 )
        W8: nVRT-Morning
    -0.59 ( 1.58 )
    -0.36 ( 1.15 )
        W8: nVRT-Noon
    -0.65 ( 1.48 )
    -0.09 ( 0.97 )
        W8: nVRT-Evening
    -0.65 ( 1.75 )
    -0.33 ( 1.19 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 < 0.001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.35
    Notes
    [11] - Superiority or legacy
    [12] - P-value is for Reaction Time Variation overall for morning, noon & evening.Primary tests were performed hierarchically to adjust for multiplicity.Reaction time variation was tested at rank 1 +ve values for mean difference are in favor of atomoxetine
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.001 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.93
    Notes
    [13] - Superiority or legacy
    [14] - P-value is for Omission Error overall for morning, noon and evening. Primary tests were performed hierarchically to adjust for multiplicity. Omission error was tested at rank 7. Positive values for the mean difference are in favor of the atomoxetine
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.001 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.65
    Notes
    [15] - Superiority or legacy
    [16] - P-value is for Mean Reaction Time overall for morning, noon and evening. Primary tests were performed hierarchically to adjust for multiplicity. Mean reaction time was tested at rank 2. +ve values for mean difference are in favor of the atomoxetine
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Superiority or legacy
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 < 0.001 [18]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 0.73
    Notes
    [17] - Superiority or legacy
    [18] - P-value is for Normalized Variation of Reaction Time overall for morning, noon & evening. Primary tests were performed hierarchically to adjust for multiplicity. Normalized Variation of Reaction Time was tested at rank 10.

    Primary: Change From Baseline cb CPT Variable: Impulsivity (Includes Commission Error [CE], Anticipatory Response [AR]) Q-scores At Week 8

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    End point title
    		 Change From Baseline cb CPT Variable: Impulsivity (Includes Commission Error [CE], Anticipatory Response [AR]) Q-scores At Week 8
    End point description
    Computer test. Patient is to press button if target appears, but not at non-target. Impulsivity variables during test: CE=percent of response to non-target; ANT=percent of responses prior to target presentation. Results are converted to Q-scores (age and sex-adjusted normalized scores with a mean=0 and standard deviation=1 in the general population, expressing the probability determined by the Gamma function in terms of standard deviation of Gaussian density). Higher scores reflect more severe symptoms.
    End point type
    Primary
    End point timeframe
    Baseline, 8 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    63
    62
    Units: Q-scores
    arithmetic mean (standard deviation)
        Baseline: CE- Morning
    -0.68 ( 1.34 )
    -0.89 ( 1.03 )
        Baseline: CE- Noon
    -0.65 ( 1.29 )
    -0.85 ( 0.94 )
        Baseline: CE- Evening
    -0.80 ( 1.23 )
    -0.87 ( 1.06 )
        W8: CE- Morning
    -0.88 ( 1.33 )
    -0.32 ( 0.90 )
        W8: CE- Noon
    -0.94 ( 1.33 )
    -0.44 ( 0.82 )
        W8: CE- Evening
    -0.76 ( 1.31 )
    -0.49 ( 0.92 )
        Baseline: AR- Morning
    0.41 ( 1.15 )
    0.15 ( 0.88 )
        Baseline: AR- Noon
    0.28 ( 1.06 )
    0.12 ( 0.85 )
        Baseline: AR- Evening
    0.32 ( 1.16 )
    0.08 ( 0.85 )
        W8: AR- Morning
    -0.50 ( 0.98 )
    -0.34 ( 0.84 )
        W8: AR-Noon
    -0.54 ( 0.87 )
    -0.31 ( 0.84 )
        W8: AR- Evening
    -0.52 ( 0.83 )
    -0.28 ( 0.78 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 < 0.001 [20]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 0.68
    Notes
    [19] - Superiority or legacy
    [20] - P-value is for Commission Error overall for morning, noon and evening. Primary tests were performed hierarchically to adjust for multiplicity. Commission Error was tested at rank 4. Positive values for mean difference are in favor of the atomoxetine
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.022 [22]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.31
    Notes
    [21] - Superiority or legacy
    [22] - P-value is for Anticipatory Response overall for morning, noon and evening. Anticipatory Response was not tested in the primary analysis but is a secondary endpoint. Positive values for the mean difference are in favor of the atomoxetine arm.

    Primary: Change From Baseline cb CPT Variable: Other (Includes Error Rate [ER] and Multi Response [MR]) Q-scores At Week 8

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    End point title
    		 Change From Baseline cb CPT Variable: Other (Includes Error Rate [ER] and Multi Response [MR]) Q-scores At Week 8
    End point description
    Computer test. Patient is to press button if target appears, but not at non-target. Other variables during test: ER=percent of overall incorrect responses (CE and OE); MR=percent of multiple responses per presentation of target (patient responds more than once to target). Results are converted to Q-scores (age and sex-adjusted normalized scores with a mean=0 and standard deviation=1 in the general population, expressing the probability determined by the Gamma function in terms of standard deviation of Gaussian density). Higher scores reflect more severe symptoms. APD: Full analysis population (N=125) including all randomized participants taking at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline, 8 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    63
    62
    Units: Q-scores
    arithmetic mean (standard deviation)
        Baseline: ER- Morning
    0.37 ( 1.56 )
    0.30 ( 1.15 )
        Baseline: ER- Noon
    0.52 ( 1.46 )
    0.41 ( 1.24 )
        Baseline: ER- Evening
    0.37 ( 1.58 )
    0.41 ( 1.24 )
        W8: ER- Morning
    -0.41 ( 2.06 )
    0.35 ( 1.10 )
        W8: ER- Noon
    -0.44 ( 1.70 )
    0.32 ( 1.06 )
        W8: ER- Evening
    -0.43 ( 1.80 )
    0.28 ( 1.10 )
        Baseline: MR- Morning
    -0.04 ( 1.25 )
    -0.26 ( 0.84 )
        Baseline: MR- Noon
    0.01 ( 1.15 )
    -0.30 ( 0.95 )
        Baseline: MR- Evening
    0.03 ( 1.25 )
    -0.34 ( 0.89 )
        W8: MR- Morning
    -0.23 ( 1.15 )
    -0.24 ( 0.78 )
        W8: MR- Noon
    -0.45 ( 0.97 )
    -0.16 ( 0.83 )
        W8: MR- Evening
    -0.35 ( 1.30 )
    -0.16 ( 0.77 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 < 0.001 [24]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.18
    Notes
    [23] - Superiority or legacy
    [24] - P-value is for Error Rate overall for morning, noon and evening. Error Rate was not tested in the primary analysis but is a secondary endpoint. Positive values for the mean difference are in favor of the atomoxetine arm.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Superiority or legacy
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.178 [26]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 0.28
    Notes
    [25] - Superiority or legacy
    [26] - P-value is for Multi Response overall for morning, noon and evening. Multi Response was not tested in the primary analysis but is a secondary endpoint. Positive values for the mean difference are in favor of the atomoxetine arm.

    Secondary: Change From Baseline Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered And Scored (ADHDRS-IV-Parent:Inv) Total Score At Week 8

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    End point title
    		 Change From Baseline Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered And Scored (ADHDRS-IV-Parent:Inv) Total Score At Week 8
    End point description
    Measures the 18 symptoms contained in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of Attention-Deficit/Hyperactivity Disorder. Individual item scores range from 0 (none/never or rarely) to 3 (severe/very often). Total scores range from 0 to 54. APD: Full analysis population (N=125) including all randomized participants taking at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    63
    62
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline to Visit 7 (Week 8)
    -17.19 ( 15.63 )
    -4.76 ( 11.51 )
        Baseline to LOCF
    -15.78 ( 15.19 )
    -4.21 ( 10.89 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Comparison of atomoxetine vs. placebo at Visit 7 (Week 8).
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 < 0.001 [28]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    11.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.2
         upper limit
    		 14.99
    Notes
    [27] - Superiority or legacy
    [28] - P-value for ADHD-RS Total Score. Positive values for the mean difference are in favor of the atomoxetine arm.

    Secondary: Change From Baseline Clinical Global Impressions-Severity of ADHD (CGI-S-ADHD) Score at Week 8

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    End point title
    		 Change From Baseline Clinical Global Impressions-Severity of ADHD (CGI-S-ADHD) Score at Week 8
    End point description
    CGI-S-ADHD measures severity of the patient's overall severity of ADHD symptoms (1=normal, not at all ill; 7=among the most extremely ill patients). APD: Full analysis population (N=125) including all randomized participants taking at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    63
    62
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline to Visit 7 (Week 8)
    -1.78 ( 1.61 )
    -0.63 ( 1.11 )
        Baseline to LOCF
    -1.52 ( 1.63 )
    -0.40 ( 1.17 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Comparison of atomoxetine vs. placebo at Visit 7 (Week 8).
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 < 0.001 [30]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.46
    Notes
    [29] - Superiority or legacy
    [30] - P-value for CGI-S ADHD score. Positive values for the mean difference are in favor of the atomoxetine arm.

    Secondary: Change From Baseline Weekly Rating Of Evening and Morning Behavior-Revised-Investigator Rated, Total and Subscores at Week 8

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    End point title
    		 Change From Baseline Weekly Rating Of Evening and Morning Behavior-Revised-Investigator Rated, Total and Subscores at Week 8
    End point description
    Weekly Rating Of Evening & Morning Behavior-Revised-Investigator Rated (WREMB-R-Inv) measures the level of difficulty of 11 common morning or evening behaviors (e.g. getting out of bed, doing homework, sitting through dinner). Possible scores for each item range from 0 (no difficulty) to 3 (a lot of difficulty) with a Total score (maximum score=33), Morning subscore (maximum score=9), Evening subscore (maximum score=24), and Item 11 score which pertains to degree of difficulty falling asleep (maximum score=3). APD: Full analysis population (N=125) including all randomized participants taking at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    63
    62
    Units: units on a scale
    arithmetic mean (standard deviation)
        Total Score: Baseline to Visit 7 (Week 8)
    -10.72 ( 10.21 )
    -5.10 ( 6.83 )
        Total Score: Baseline to LOCF
    -9.59 ( 9.98 )
    -3.90 ( 7.83 )
        Evening Subscore: Baseline to Visit 7 (Week 8)
    -6.91 ( 6.38 )
    -3.57 ( 4.36 )
        Evening Subscore: Baseline to LOCF
    -6.30 ( 6.21 )
    -3.03 ( 5.18 )
        Morning Subscore: Baseline to Visit 7 (Week 8)
    -2.81 ( 3.04 )
    -1.16 ( 2.74 )
        Morning Subscore: Baseline to LOCF
    -2.46 ( 3.00 )
    -0.65 ( 2.94 )
        Item 11 Subscore: Baseline to Visit 7 (Week 8)
    -1.00 ( 1.60 )
    -0.37 ( 1.00 )
        Item 11 Subscore: Baseline to LOCF
    -0.83 ( 1.60 )
    -0.23 ( 1.05 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 < 0.001 [32]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.55
         upper limit
    		 7.92
    Notes
    [31] - Superiority or legacy
    [32] - P-value for Total Score. Positive values for the mean difference are in favor of the atomoxetine arm.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Atomoxetine
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 = 0.001 [34]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.49
         upper limit
    		 5.44
    Notes
    [33] - Superiority or legacy
    [34] - P-value for Evening subscore. Positive values for the mean difference are in favor of the atomoxetine arm.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 < 0.002 [36]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.93
    Notes
    [35] - Superiority or legacy
    [36] - P-value for Morning subscore. Positive values for the mean difference are in favor of the atomoxetine arm.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 < 0.001 [38]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 0.93
    Notes
    [37] - Superiority or legacy
    [38] - P-value for Item 11 (difficulty falling asleep). Positive values for the mean difference are in favor of the atomoxetine arm.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Atomoxetine
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Atomoxetine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Atomoxetine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 63 (50.79%)
    27 / 62 (43.55%)
    Nervous system disorders
    Headache
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 63 (4.76%)
    5 / 62 (8.06%)
         occurrences all number
    3
    5
    General disorders and administration site conditions
    Fatigue
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    4 / 63 (6.35%)
    1 / 62 (1.61%)
         occurrences all number
    4
    2
    Pyrexia
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 63 (4.76%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Abdominal pain
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    7 / 63 (11.11%)
    2 / 62 (3.23%)
         occurrences all number
    8
    2
    Abdominal pain upper
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    2 / 63 (3.17%)
    3 / 62 (4.84%)
         occurrences all number
    2
    3
    Nausea
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    6 / 63 (9.52%)
    2 / 62 (3.23%)
         occurrences all number
    7
    2
    Vomiting
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 63 (4.76%)
    2 / 62 (3.23%)
         occurrences all number
    3
    2
    Respiratory, thoracic and mediastinal disorders
    Pharyngolaryngeal pain
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    4 / 63 (6.35%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Psychiatric disorders
    Aggression
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    0 / 63 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    5
    Infections and infestations
    Influenza
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    0 / 63 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    4
    Nasopharyngitis
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 63 (4.76%)
    2 / 62 (3.23%)
         occurrences all number
    3
    2
    Respiratory tract infection
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 63 (1.59%)
    3 / 62 (4.84%)
         occurrences all number
    1
    3
    Upper respiratory tract infection
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    4 / 63 (6.35%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Metabolism and nutrition disorders
    Anorexia
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 63 (4.76%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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